In vivo pretreatment with leupeptin (an inhibitor of thiol-proteases) markedly reduced cellular proteolysis (measured as tyrosine production) in slices of normal (-42%) and ischemic (-73%) rat ventricular myocardium incubated in vitro. However, the same doses of leupeptin failed to reduce infarct size (determined histologically) in rats. Thus, thiol-proteases (lysosomal cathepsins B, H and L and cytoplasmic (Ca-activated protease) do not appear to contribute to ischemic cell death.